Morpholine carboxamides and use thereof

ABSTRACT

1-Hydroxyphenoxy-3-ureidoethylamino-2-propanol derivatives, processes for their manufacture, pharmaceutical compositions containing them and methods of using them in the treatment of heart failure. The compounds possess cardio-selective β-adrenergic stimulant activity. Representative of the compounds disclosed is 1-p-hydroxyphenoxy-3-β-(morpholinocarbonamido)ethylamino-2-propanol.

This invention relates to cardiac stimulants and more particularly itrelates to novel alkanolamine derivatives which possess said property.

In United Kingdom Pat. No. 1,455,116 there are described and claimedinter alia alkanolamine derivatives of the formula: ##STR1## wherein Ymay be an imino, alkylimino, iminoalkylene or iminoalkyleneoxy radicaland R¹ may be hydrogen or a hydrocarbon radical such as an alkyl,alkenyl, cycloalkyl or aryl radical. These compounds are stated to have,in addition to β-adrenergic blocking activity, substantial cardiacstimulant activity. This definition does not include within its scopecompounds wherein Y is a disubstituted imino radical and the substituentR¹ is an aliphatic substituent in which the total group --YR¹ containsan oxygen atom.

It is believed that an ideal cardiac stimulant should produce in a dogwith cardiac reflexes removed an increase in heart rate of about onehalf of the increase produced under similar conditions by isoprenaline,preferably between 45% and 60% of that produced by isoprenaline; that itshould exert this heart-rate-increasing effect at a low oral dose; andthat at said low oral dose it should be substantially devoid of theblood-pressure-lowering effect which is exerted by isoprenaline at acorresponding dose. No compound specifically exemplified in UnitedKingdom Specification No. 1,455,116 has exactly this balance ofproperties, which are hereinafter referred to as cardio-selectiveβ-ardrenergic stimulant properties, although many compounds described insaid specification do indeed possess substantial cardiac stimulantproperties.

We have now found, and herein lies our invention, that certain compoundswhich are closely related to the compounds described in saidspecification, but which are outside the scope of the claims thereof, dopossess the desired balance of cardioselective β-adrenergic stimulantproperties.

According to the invention there is provided an alkanolamine derivativeof the formula: ##STR2## wherein R³ and R⁴, which may be the same ordifferent, each is hydrogen or a hydroxy radical, provided that at leastone of R³ and R⁴ is a hydroxy radical, and wherein either R is hydrogen,methyl or ethyl and R² is methyl, ethyl or a radical of the formula--CH₂ CH₂ OR, wherein R has the meaning stated above, or R and R² arejoined together to form the ethylene (--CH₂ CH₂ --) radical; or anacid-addition salt thereof.

It will be observed that the alkanolamine derivative of the inventionpossesses an asymmetric carbon atom, namely the carbon atom of the--CHOH-- group in the alkanolamine side-chain, and it can thereforeexist in racemic and optically-active forms. It is to be understood thatthis invention encompasses the racemic form of the alkanolaminederivative and any optically-active form which possesses β-adrenergicstimulant activity, it being a matter of common general knowledge how aracemic compound may be resolved into optically-active forms, and howthe β-adrenergic stimulant activity of these forms may be determined. Itis further to be understood that β-adrenergic stimulant activity usuallypredominates in that optically-active form which has the "S" absoluteconfiguration of the said --CHOH-- group.

A suitable acid-addition salt of an alkanolamine derivative of theinvention is, for example, a salt derived from an inorganic acid, forexample a hydrochloride, hydrobromide, phosphate or sulphate, or a saltderived from an organic acid, for example an oxalate, fumarate, lactate,tartrate, acetate, salicylate, citrate, benzoate, β-naphthoate, adipateor 1,1-methylene-bis-(2-hydroxy-3-naphthoate), or a salt derived from anacidic synthetic resin, for example a sulphonated polystyrene resin.

Specific alkanolamine derivatives of the invention are those hereinafterdescribed in the Examples. Of these, a preferred compound is1-(p-hydroxyphenoxy)-3-β-(morpholino-carbonamido) ethylamino-2-propanol,especially the S-(-)-isomer thereof or an acid-addition salt thereof.

The alkanolamine derivative of the invention may be manufactured by anychemical process known to be useful for the manufacture ofchemically-analogous compounds, and in particular may be manufactured byany of the processes described for the manufacture of similar compoundsin United Kingdom Pat. No. 1,455,116.

According to a further feature of the invention there is provided aprocess for the manufacture of the alkanolamine derivative of theinvention which comprises assembling in sequence, by chemical methodspublically-known for such purpose, the six radicals:

(i) an aryloxy radical of the formula: ##STR3## wherein R¹³ and R¹⁴,which may be the same or different, each stands for hydrogen or for aradical of the formula R⁵ O-- wherein R⁵ stands for hydrogen or for aprotecting group, provided that at least one of R¹³ and R¹⁴ is a radicalof the formula R⁵ O--;

(ii) a radical of the formula: ##STR4## wherein R⁶ stands for hydrogenor for a protecting group; (iii) a radical of the formula --NR⁷ --,wherein R⁷ stands for hydrogen or for a protecting group;

(iv) a radical of the formula --CH₂ CH₂ NR⁸ -- wherein R⁸ stands forhydrogen or for a protecting group;

(v) a carbonyl (--CO--) radical; and

(vi) a radical of the formula ##STR5## wherein R and R² have themeanings stated above; whereafter if one or more of R⁵, R⁶, R⁷ and R⁸stands for a protecting group the one or more protecting groups areremoved.

The various stages of the assembly may be carried out in any possibleorder, and in particular any of the sequences of reactions described inUnited Kingdom Pat. No. 1,455,116 may be applied to the synthesis of thealkanolamine derivatives of the present invention. The protecting groupsR⁶, R⁷ and R⁸ may be similar to the corresponding protecting groupsdescribed in said specification, and R⁵ when a protecting group ispreferably the benzyl radical.

One preferred process for the manufacture of the alkanolamine derivativeof the invention comprises the reaction of a compound of the formula:##STR6## wherein R⁶, R¹³ and R¹⁴ have the meanings stated above andwherein Z stands for a displaceable radical, with an amine of theformula:

    HNR.sup.2 --CH.sub.2 CH.sub.2 OR

wherein R and R² have the meanings stated above, followed by removal ofany protecting group present. R⁶ is preferably the benzyl radical andone or both of R¹³ and R¹⁴ is preferably the benzyloxy radical, thebenzyl radicals being removed by hydrogenolysis.

A second preferred process for the manufacture of the alkanolaminederivative of the invention comprises the reaction of a compound of theformula: ##STR7## wherein R¹³ and R¹⁴ have the meanings stated above,with a compound of the formula: ##STR8## wherein R, R² and R⁶ have themeanings stated above, followed by the removal of any protecting grouppresent. R⁶ is preferably hydrogen and one or both of R¹³ and R¹⁴ ispreferably the benzyloxy radical, the benzyl part of this being removedof hydrogenolysis. Optically-active enantiomorphs of the alkanolaminederivative of the invention may be obtained by the resolution byconventional means of the corresponding racemic alkanolamine derivativeof the invention.

The said resolution may be carried out by reacting the racemicalkanolamine derivative with an optically-active acid, followed byfractional crystallisation of the diastereoisomeric mixture of saltsthus obtained from a diluent or solvent, for example ethanol, whereafterthe optically-active alkanolamine derivative is liberated from the saltby treatment with a base. A suitable optically-active acid is, forexample, (+)- or (-)-O,O-di-p-toluoyltartaric acid or (-)-2,3:4,5-di-O-isopropylidene-2-keto-L-gulonic acid.

The resolution process may be facilitated by treating the partiallyresolved alkanolamine derivative in free base form obtained after asingle fractional crystallisation of the diastereoisomeric mixture ofsalts with a solubilising agent, for example a primary amine, forexample allylamine, in a relatively non-polar diluent or solvent, forexample petroleum ether.

The alkanolamine derivative of the invention in free base form may beconverted into an acid-addition salt thereof by reaction with an acid byconventional means.

As stated above, the alkanolamine derivative of the invention or anacid-addition salt thereof possesses β-adrenergic stimulant activity,and furthermore this activity is cardioselective. The activity may bedemonstrated by the increase in heart rate produced by administration ofthe compound to a dog, pretreated with syrosingopine to removecatecholamines, in which the vagal nerves have been cut in order toisolate the heart, and the absence of decrease in blood pressure in adenervated hind limb of the same dog when the limb is perfused atconstant volume blood flow. Unlike isoprenaline, a known cardiacstimulating agent which is not cardioselective, a preferred alkanolaminederivative of the invention or a salt thereof is well absorbed whenadministered orally and has a substantial duration of action. At dosesof an alkanolamine derivative of the invention which produce effectivecardiac stimulation in dogs, no symptoms of toxicity are apparent.

The alkanolamine derivative of the invention may be administered towarm-blooded animals, including man, in the form of a pharmaceuticalcomposition comprising as active ingredient at least one alkanolaminederivative of the invention, or an acid-addition salt thereof, inassociation with a pharmaceutically-acceptable diluent or carriertherefor.

A suitable composition is, for example, a tablet, capsule, aqueous oroily solution or suspension, emulsion, injectable aqueous or oilysolution or suspension, dispersible powder, spray or aerosolformulation.

The pharmaceutical composition may contain, in addition to thealkanolamine derivative of the invention, one or more drugs selectedfrom sedatives, for example phenobarbitone, meprobamate, chlorpromazineand the benzodiazepine sedative drugs, for example chlordiazepoxide anddiazepam; vasodilators, for example glyceryl trinitrate, pentaerythritoltetranitrate and isosorbide dinitrate; diuretics, for examplechlorothiazide; hypotensive agents, for example reserpine, bethanidineand guanethidine; cardiac membrane stabilising agents, for examplequinidine; agents used in the treatment of Parkinson's disease and othertremors, for example benzhexol; cardiotonic agents, for exampledigitalis preparations; α-adrenergic blocking agents, for examplephentolamine and sympathomimetic bronchodilators, for exampleisoprenaline, orciprenaline, adrenaline and ephedrine.

When used for the treatment of acute or chronic heart failure in man, itis expected that the alkanolamine derivative would be given to man at atotal oral dose of between 10 mg. and 200 mg. daily, at doses spaced at6-8 hourly intervals, or at an intravenous dose of between 1 mg. and 100mg.

Preferred oral dosage forms are tablets or capsules containing between10 and 100 mg., and preferably 10 mg. or 50 mg. of active ingredient.Preferred intravenous dosage forms are sterile aqueous solutions of thealkanolamine derivative or of a non-toxic acid-addition salt thereof,containing between 0.05% and 1% w/v of active ingredient, and moreparticularly containing 0.1% w/v of active ingredient.

The invention is illustrated but not limited by the following Examples:

EXAMPLE 1

Sodium bicarbonate (2.5 g.) and then phenyl chloroformate (1.6 g.) areadded to a stirred solution of3-N-(β-aminoethyl)-N-benzylamino-1-(p-benzyloxyphenoxy)-2-propanol (4.06g.) in toluene (15 ml.), the temperature of the mixture rising to 50° C.Water is added, the mixture is filtered and the solid product is washedwith toluene and dried. There is thus obtained3-N-(β-phenoxycarbonamidoethyl)-N-benzylamino-1-(p-benzyloxyphenoxy)-2-propanol,m.p. 63°-65° C.

A mixture of the above compound (2.63 g.), morpholine (0.48 g.) andtoluene (25 ml.) is heated at 100° C. for 72 hours, cooled and dilutedwith ether. The mixture is washed with aqueous 2N-Sodium hydroxidesolution and then with water, dried and evaporated to dryness underreduced pressure. The residue is dissolved in a mixture of ethanol (20ml.) and acetic acid (20 ml.), a 30% palladium-on-charcoal catalyst (0.1g.) is added and the mixture is shaken with hydrogen at laboratorytemperature and pressure until 250 ml. of hydrogen have been absorbed.The mixture is filtered, the filtrate is evaporated to dryness underreduced pressure and the residue is dissolved in ethanol. An excess of asaturated solution of oxalic acid in ethanol is added, the mixture isfiltered and the solid product is washed with boiling ethanol and thendried. There is thus obtained1-(p-hydroxyphenoxy)-3-β-(morpholinocarbonamido)ethylamino-2-propanolhydrogen oxalate, m.p. 168°-169° C. (with decomposition).

The process described above is repeated except that the appropriatem-benzyloxyphenoxy compound is used in place of the p-benzyloxyphenoxycompound. There is thus obtained1-(m-hydroxyphenoxy)-3-β-(morpholinocarbonamido) ethylamino-2-propanolhydrogen oxalate, m.p. 122°-126° C.

EXAMPLE 2

The process described in Example 1 is repeated except that theappropriate secondary amine is used in place of morpholine. There arethus obtained the compounds described in the following table:

    __________________________________________________________________________     ##STR9##                                                                     R      R.sup.2   Salt      m.p.(° C.)                                  __________________________________________________________________________    H      methyl    hydrochloride                                                                           (oil)                                                               dihydrate                                                    methyl methyl    hydrogen  158-160                                                             oxalate                                                      H      ethyl     hydrogen  149-151                                                             oxalate                                                                       hemihydrate                                                  H      β-hydroxyethyl                                                                     hydrochloride                                                                           (oil)                                                               trihydrate                                                   __________________________________________________________________________

EXAMPLE 3

A suspension of 1-p-benzyloxyphenoxy-2,3-epoxypropane (11.5 g.) inisopropanol (6ml.) is added to a stirred mixture of4-(N-β-aminoethylcarbamoyl) morpholine hydrogen sulphate (12.7 g.),potassium hydroxide (7.0 g.) and isopropanol (10 ml.) and the mixture isstirred at 45° C. for 1 hour and then evaporated to dryness underreduced pressure. The residual oil is stirred with water, the mixture isfiltered and the solid residue is dissolved in acetone. A 30% w/wsolution of hydrogen chloride in propanol is added until the pH of themixture is less than 2, and the mixture is filtered. The solid residueis crystallised from water and there is thus obtained1-p-benzyloxyphenoxy-3-(β-morpholinocarbonamidoethyl)amino-2-propanolhydrochloride (4.9 g.).

A solution of the above compound in a mixture of ethanol (20 ml.) andacetic acid (20 ml.) is shaken with a 30% palladium-on-charcoal catalyst(0.1 g.) in an atmosphere of hydrogen at laboratory temperature andpressure until 250 ml. of hydrogen is absorbed. The mixture is filtered,the filtrate is evaporated to dryness under reduced pressure and to theresidue is added a hot solution of fumaric acid (1.25 g.) in ethanol (15ml.). The mixture is kept at 5° C. for 12 hours and is then filtered,and the solid residue is washed with hot ethanol and then dried. Thereis thus obtained1-p-hydroxyphenoxy-3-β-(morpholinocarbonamido)ethyl-amino-2-propanolhydrogen fumarate, m.p. 168°-169° C. (with decomposition).

The 4-(N-β-aminoethylcarbamoyl)morpholine hydrogen sulphate used asstarting material may be obtained as follows:

Morpholine (4.35 g.) and phenyl chloroformate (6.35 g.) are separatelyand simultaneously added dropwise during 20 minutes to a stirred mixtureof toluene (10 ml.), water (5 ml.) and sodium hydroxide (2 g.) which ismaintained at 0° C. The mixture is stirred for a further 2 hours whilstthe temperature is allowed to rise to 20° C. The toluene solution isseparated, the aqueous solution is extracted twice with toluene (50 ml.each time) and the combined toluene solutions are washed with water,dried and evaporated to dryness under reduced pressure. The residue iscrystallised from petroleum ether (b.p. 60°-80° C.) and there is thusobtained N-phenoxycarbonylmorpholine, m.p. 46.5°-47.5° C.

A mixture of the above compound (11 g.) and ethylenediamine (27.8 g.) isstirred at laboratory temperature for 3 days and the excess of ethylenediamine is removed by evaporation under reduced pressure. The residue isdissolved in methanol, the solution is cooled to 5° C. and concentratedsulphuric acid is added until the pH of the solution is 2. A filter-aid(`Celite`, 10 g.; `Celite` is a Trade Mark) is added and the mixture isstirred for 1 hour and then filtered. The filtrate is evaporated todryness under reduced pressure and the residue is stirred with ethylacetate. The mixture is filtered and there is thus obtained as solidresidue 4-(N-β-aminoethylcarbamoyl)morpholine hydrogen sulphate, m.p.168°-169° C.

EXAMPLE 4

A mixture ofR-(-)-1-p-benzyloxyphenoxy-3-p-toluene-sulphonyloxy-2-propanol (8.56g.), β-(morpholinocarbonamido)-ethylamine (8.76 g.) isopropanol (40 ml.)and aqueous 2N-sodium hydroxide solution (10 ml.) is heated under refluxfor 16 hours, cooled and poured into a mixture of water and ethylacetate. The organic layer is separated, dried and diluted withpetroleum ether (b.p. 60°-80° C.), and the mixture is filtered. Theresidue is crystallised from a mixture of ethyl acetate and petroleumether (b.p. 60°-80° C.) and is then purified by chromatography on asilica column (200 g.) using methanol as eluant. There is thus obtained(S)-1-p-benzyloxyphenoxy-3-β-(morpholinocarbonamido)ethylamino-2-propanol.A solution of the above compound (1.2 g.) in acetic acid is shaken witha 30% palladium-on-charcoal catalyst (50 mg.) at laboratory temperatureand atmospheric pressure until 90 ml. of hydrogen have been absorbed.The mixture is filtered, the filtrate is evaporated to dryness and theresidue is dissolved in ethanol. A molar solution of oxalic acid inethanol (5 ml.) is added and the mixture is set aside to crystallise.The mixture is filtered and the solid product is recrystallised from amixture of methanol and ethyl acetate. There is thus obtainedS-(-)-1-p-hydroxyphenoxy-3-β-(morpholinocarbonamido)ethylamino-2-propanol hydrogen oxalate, m.p. 150-151° C. [α]_(D) ²⁰ =-6.2° (c, 5% in water).

The R-(-)-1-p-benzyloxyphenoxy-3-p-toluenesulphonyloxy-2-propanol usedas starting material may be obtained as follows:

A mixture of glycerol 1,2-acetonide (66 g.) and phthalic anhydride (74g.) is heated at 100° C. for 18 hours and then cooled. The combinedsyrupy product from three such reactions (415 g.) is dissolved inisopropanol (2.5 liters), (-)-α-methylbenzylamine (148.1 g.) is addedand the mixture is kept at laboratory temperature for 4 hours and thenfiltered. The solid product is crystallised twice from isopropanol (4liters each time) and there is thus obtained (-)-α-methylbenzylamineo-(2,3-isopropylidenedioxypropoxycarbonyl)benzoate, m.p. 153.5° C.

A solution of the above compound (126.5 g.) in chloroform is shaken withdilute aqueous hydroxchloric acid, and the chloroform layer isseparated, washed with water, dried and evaporated to dryness. A mixtureof the residue (84.2 g.), water (200 ml.) and aqueous 10N-sodiumhydroxide solution (50 ml.) is heated at 100° C. for 10 minutes, cooledand extracted 5 times with ether. The combined ethereal extracts arewashed with water, dried and evaporated to dryness, and the residue isdistilled under reduced pressure. There is thus obtained(R)-(-)-glycerol 1,2-acetonide, b.p. 84° C./12 mm. Hg, [α]_(D) ²⁰ =-9.2° (c, 10% in methanol).

The above compound (32.4 g.) is added to a stirred, cooled mixture ofp-toluene-sulphonyl chloride (46.8 g.) in pyridine (25 ml.) and themixture is stirred for 1 hour and then poured into water. The aqueousmixture is extracted with ether and the extract is washed with water,dried and evaporated to dryness. The residue is crystallised twice frompetroleum ether (b.p. 60-80° C.) at -78° C., and there is thus obtainedS-(+)-3-p-toluenesulphonylglycerol 1,2-acetonide, [α]_(D) ²⁰ = + 3.1°(c, 10% in methanol).

The above compound is converted toR-(-)-1-p-benzyloxyphenoxy-3-p-toluenesulphonyloxy-2-propanol (m.p.90-91° C., [α]_(D) ²⁰ = - 9.1° (c, 20% in ethylacetate) by reaction withp-benzyloxyphenol and hydrolysis of the isopropylidenedioxy group;treatment of the (S)-(+)-3-O-p-benzyloxyphenyl)-glycerol [m.p. 122-123°C., [α]_(D) ²⁰ = + 4.3° (c, 4.5% in methanol)] thus obtained withp-toluenesulphonyl chloride; and crystallisation of the product obtainedfrom aqueous isopropanol, by a similar process to that described in theJournal of Medicinal Chemistry, 1973, 16, 168-169 for the preparation ofS-(+)-1-(4-acetamidophenoxy)-3-(4-toluenesulphonyloxy)propan-2-ol fromR-(-)-α-(4-toluenesulphonyl)acetone glycerol.

What we claim is:
 1. An alkanolamine derivative selected from the groupconsisting of a compound of the formula: ##STR10## wherein R³ and R⁴,which may be the same or different, each is hydrogen or hydroxy,provided that at least one of R³ and R⁴ is hydroxy, and wherein R and R²are joined together to form ethylene (--CH₂ CH₂ --); and non-toxic,pharmaceutically-acceptable acid-addition salts thereof. 2.1-(p-Hydroxyphenoxy)-3-.beta.-(morpholinocarbonamido)ethylamino-2-propanolor a non-toxic, pharmaceutically-acceptable acid-addition salt thereof.3.S-(-)-1-(p-hydroxyphenoxy)-3-β-(morpholinocarbonamido)ethylamino-2-propanolor a non-toxic, pharmaceutically-acceptable acid-addition salt thereof.4. An acid-addition salt as claimed in claim 1, which is ahydrochloride, hydrobromide, phosphate, sulphate, oxalate, fumarate,lactate, tartrate, acetate, salicylate, citrate, benzoate, β-naphthoate,adipate or 1,1-methylene-bis-(2-hydroxy-3-naphthoate), or a salt derivedfrom a sulphonated polystyrene resin.
 5. A pharmaceutical compositioncomprising as active ingredient a cardio selective stimulating amount ofat least one alkanolamine derivative or an acid-addition salt thereof,claimed in claim 1, in association with a pharmaceutically-acceptablediluent or carrier therefor.
 6. A composition as claimed in claim 5which is in the form of a tablet, capsule, aqueous or oily solution orsuspension , emulsion, injectable aqueous or oily solution orsuspension, dispersible powder, spray or aerosol formulation.
 7. Acomposition as claimed in claim 5 which contains, in addition to thealkanolamine derivative, one or more drugs selected from sedatives,vasodilators, diuretics, hypotensive agents, cardiac membranestabilising agents, agents used in the treatment of Parkinson's disease,cardiotonic agents, α-adrenergic blocking agents and sympathomimeticbronchodilators.
 8. A method for the treatment of acute or chronic heartfailure in a warm-blooded animal which comprises administering to saidanimal an effective amount of at least one compound claimed in claim 1.